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Molecular Genetics of Infertility
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Molecular Genetics of Infertility

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 7277

Special Issue Editors

Dr. Eisa Tahmasbpour Marzouni

E-Mail Website
Guest Editor
St Vincent's Hospital, Darlinghurst, Sydney, NSW 2010, Australia
Interests: spermatogenesis; male infertility; stem cells; regenerative medicine; reproductive biology
Dr. Sylvie Jaillard

E-Mail Website
Guest Editor
1. CHU Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) – UMR_S 1085, Université Rennes, F-35000 Rennes, France
2. CHU Rennes, Service de Cytogénétique et Biologie Cellulaire, F-35033 Rennes, France
Interests: cytogenetic; chromosomal rearrangements; high-throughput sequencing; genetics of infertility; premature ovarian failure
Dr. Elena J. Tucker

E-Mail Website
Guest Editor
Murdoch Childrens Research Institute, MCRI, Department of Paediatrics, University of Melbourne, Parkville, VIC 3010, Australia
Interests: genomics; premature ovarian insufficiency; infertility; mitochondria; sex development

Special Issue Information

Dear Colleagues,

We would like to invite you to contribute manuscripts dedicated to the “Molecular Genetics of Infertility” for this Special Issue of Genes. In this Special Issue, we would like to focus on the molecular genetic factors associated with the abnormal development of male and female sex organs, leading to impaired spermatogenesis/ovarian disease and infertility, as well as the potential use of innovative therapies, such as stem cells, for treatment.

Genetic factors are known to be responsible for about 15 to 30% of infertility cases, and it can be assumed that most cases of currently unexplained infertility may also have a genetic basis. Some of these abnormalities may transmit to offspring via assisted reproductive techniques (ARTs), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and result in the birth of children with a higher risk of infertility and congenital abnormalities. Therefore, the identification of these abnormalities in the context of human reproductive development and infertility is worthwhile for andrologists, endocrinologists, and related clinicians prior to therapeutic procedures. Moreover, we would also like to focus on the importance of stem cells in reproductive development. Stem cell technology has opened a new door for the treatment of several developmental diseases, and recent advances have demonstrated the potential regeneration or production of sex organoids using stem cells. Therefore, it appears that these cells can be considered as a valuable and innovative strategy for the treatment of infertility, especially for those who suffer from abnormal sex organ development.  

This Special Issue offers an opportunity to address the following, but other topics are welcomed and considered:

  • Common and rare genetic syndromes associated with the abnormal development of sex organs and/or infertility.
  • Role of molecular genetic factors in ovarian disease.
  • Role of molecular genetic factors in impaired spermatogenesis.
  • Role of molecular genetic factors in assisted reproductive techniques.
  • The importance of genes and variants in reproductive development and function.
  • Role of epigenetic modifications in reproductive development and function.
  • The importance of stem cells in infertility treatment.
  • Regenerative medicine and infertility.

Your contribution is welcome in the form of an original research article, case report, commentary, and/or review.

Let us share our experiences to take better care of patients with reproductive disorders.

Kind regards,

Dr. Eisa Tahmasbpour Marzouni
Dr. Sylvie Jaillard
Dr. Elena J. Tucker
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • infertility
  • ovarian disease
  • impaired spermatogenesis
  • reproductive development and function
  • molecular genetics
  • genes and variants
  • epigenetic modifications

Published Papers (5 papers)

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Research

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17 pages, 5006 KiB  
Article
A Human Homozygous HELQ Missense Variant Does Not Cause Premature Ovarian Insufficiency in a Mouse Model
by Shabnam Bakhshalizadeh, Anthony D. Bird, Rajini Sreenivasan, Katrina M. Bell, Gorjana Robevska, Jocelyn van den Bergen, Mohammad Asghari-Jafarabadi, Andrew J. Kueh, Philippe Touraine, Anna Lokchine, Sylvie Jaillard, Katie L. Ayers, Dagmar Wilhelm, Andrew H. Sinclair and Elena J. Tucker
Genes 2024, 15(3), 333; https://doi.org/10.3390/genes15030333 - 04 Mar 2024
Viewed by 880
Abstract
Disruption of meiosis and DNA repair genes is associated with female fertility disorders like premature ovarian insufficiency (POI). In this study, we identified a homozygous missense variant in the HELQ gene (c.596 A>C; p.Gln199Pro) through whole exome sequencing in a POI patient, a [...] Read more.
Disruption of meiosis and DNA repair genes is associated with female fertility disorders like premature ovarian insufficiency (POI). In this study, we identified a homozygous missense variant in the HELQ gene (c.596 A>C; p.Gln199Pro) through whole exome sequencing in a POI patient, a condition associated with disrupted ovarian function and female infertility. HELQ, an enzyme involved in DNA repair, plays a crucial role in repairing DNA cross-links and has been linked to germ cell maintenance, fertility, and tumour suppression in mice. To explore the potential association of the HELQ variant with POI, we used CRISPR/Cas9 to create a knock-in mouse model harbouring the equivalent of the human HELQ variant identified in the POI patient. Surprisingly, Helq knock-in mice showed no discernible phenotype, with fertility levels, histological features, and follicle development similar to wild-type mice. Despite the lack of observable effects in mice, the potential role of HELQ in human fertility, especially in the context of POI, should not be dismissed. Larger studies encompassing diverse ethnic populations and alternative functional approaches will be necessary to further examine the role of HELQ in POI. Our results underscore the potential uncertainties associated with genomic variants and the limitations of in vivo animal modelling. Full article
(This article belongs to the Special Issue Molecular Genetics of Infertility)
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16 pages, 1737 KiB  
Article
The Ratio of cf-mtDNA vs. cf-nDNA in the Follicular Fluid of Women Undergoing IVF Is Positively Correlated with Age
by Georgia Tsirka, Athanasios Zikopoulos, Kyriaki Papageorgiou, Charilaos Kostoulas, Ioannis Tsigkas, Efthalia Moustakli, Aris Kaltsas, Eleftheria Sarafi, Theologos M. Michaelidis and Ioannis Georgiou
Genes 2023, 14(7), 1504; https://doi.org/10.3390/genes14071504 - 23 Jul 2023
Viewed by 1287
Abstract
Age-related mitochondrial markers may facilitate the prognosis of artificial reproductive technology outcomes. In this report, we present our study concerning the ratio of cf-mtDNA/cf-nDNA, namely the amount of cell-free mitochondrial DNA relative to cell-free nuclear DNA, in the follicular fluid (FF) of women [...] Read more.
Age-related mitochondrial markers may facilitate the prognosis of artificial reproductive technology outcomes. In this report, we present our study concerning the ratio of cf-mtDNA/cf-nDNA, namely the amount of cell-free mitochondrial DNA relative to cell-free nuclear DNA, in the follicular fluid (FF) of women undergoing IVF, aiming to generate a molecular fingerprint of oocyte quality. The values of this ratio were measured and compared among three groups of women (101 in total): (A) 31 women with polycystic ovary syndrome (PCOS), (B) 34 women younger than 36 years, and (C) 36 women older than 35 years of age. Real-time quantitative PCR (qPCR) was performed to quantify the ratio by using nuclear- and mitochondrial-specific primers and analyzed for potential correlation with age and pregnancy rate. Our analysis showed that the level of FF-cf-mtDNA was lower in the group of advanced-age women than in the groups of PCOS and non-PCOS women. Moreover, a significant positive correlation between FF-cf-mtDNA and the number of mature (MII) oocytes was observed. Collectively, the data show that the relative ratio of cf- mtDNA to cf-nDNA content in human FF can be an effective predictor for assessing the corresponding oocyte’s age-related performance in IVF. Full article
(This article belongs to the Special Issue Molecular Genetics of Infertility)
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20 pages, 5005 KiB  
Article
Functional Assessment of a New PBX1 Variant in a 46,XY Fetus with Severe Syndromic Difference of Sexual Development through CRISPR-Cas9 Gene Editing
by Laura Mary, Delphine Leclerc, Audrey Labalme, Pascale Bellaud, Séverine Mazaud-Guittot, Stéphane Dréano, Bertrand Evrard, Antoine Bigand, Aurélie Cauchoix, Philippe Loget, Anna Lokchine, Laurence Cluzeau, David Gilot, Marc-Antoine Belaud-Rotureau and Sylvie Jaillard
Genes 2023, 14(2), 273; https://doi.org/10.3390/genes14020273 - 20 Jan 2023
Viewed by 1648
Abstract
Sexual development is a complex process relying on numerous genes. Disruptions in some of these genes are known to cause differences of sexual development (DSDs). Advances in genome sequencing allowed the discovery of new genes implicated in sexual development, such as PBX1. We [...] Read more.
Sexual development is a complex process relying on numerous genes. Disruptions in some of these genes are known to cause differences of sexual development (DSDs). Advances in genome sequencing allowed the discovery of new genes implicated in sexual development, such as PBX1. We present here a fetus with a new PBX1 NM_002585.3: c.320G>A,p.(Arg107Gln) variant, presenting with severe DSD along with renal and lung malformations. Using CRISPR-Cas9 gene editing on HEK293T cells, we generated a KD cell line for PBX1. The KD cell line showed reduced proliferation and adhesion properties compared with HEK293T cells. HEK293T and KD cells were then transfected plasmids coding either PBX1 WT or PBX1-320G>A (mutant). WT or mutant PBX1 overexpression rescued cell proliferation in both cell lines. RNA-seq analyses showed less than 30 differentially expressed genes, in ectopic mutant-PBX1-expressing cells compared with WT-PBX1. Among them, U2AF1, encoding a splicing factor subunit, is an interesting candidate. Overall, mutant PBX1 seems to have modest effects compared with WT PBX1 in our model. However, the recurrence of PBX1 Arg107 substitution in patients with closely related phenotypes calls for its impact in human diseases. Further functional studies are needed to explore its effects on cellular metabolism. Full article
(This article belongs to the Special Issue Molecular Genetics of Infertility)
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Review

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17 pages, 1817 KiB  
Review
Mammal Reproductive Homeobox (Rhox) Genes: An Update of Their Involvement in Reproduction and Development
by Morgane Le Beulze, Cécile Daubech, Aissatu Balde-Camara, Farah Ghieh and François Vialard
Genes 2023, 14(9), 1685; https://doi.org/10.3390/genes14091685 - 25 Aug 2023
Viewed by 1236
Abstract
The reproductive homeobox on the X chromosome (RHOX) genes were first identified in the mouse during the 1990s and have a crucial role in reproduction. In various transcription factors with a key regulatory role, the homeobox sequence encodes a “homeodomain” DNA-binding motif. In [...] Read more.
The reproductive homeobox on the X chromosome (RHOX) genes were first identified in the mouse during the 1990s and have a crucial role in reproduction. In various transcription factors with a key regulatory role, the homeobox sequence encodes a “homeodomain” DNA-binding motif. In the mouse, there are three clusters of Rhox genes (α, β, and γ) on the X chromosome. Each cluster shows temporal and/or quantitative collinearity, which regulates the progression of the embryonic development process. Although the RHOX family is conserved in mammals, the interspecies differences in the number of RHOX genes and pseudogenes testifies to a rich evolutionary history with several relatively recent events. In the mouse, Rhox genes are mainly expressed in reproductive tissues, and several have a role in the differentiation of primordial germ cells (Rhox1, Rhox6, and Rhox10) and in spermatogenesis (Rhox1, Rhox8, and Rhox13). Despite the lack of detailed data on human RHOX, these genes appear to be involved in the formation of germ cells because they are predominantly expressed during the early (RHOXF1) and late (RHOXF2/F2B) stages of germ cell development. Furthermore, the few variants identified to date are thought to induce or predispose to impaired spermatogenesis and severe oligozoospermia or azoospermia. In the future, research on the pathophysiology of the human RHOX genes is likely to confirm the essential role of this family in the reproductive process and might help us to better understand the various causes of infertility and characterize the associated human phenotypes. Full article
(This article belongs to the Special Issue Molecular Genetics of Infertility)
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Other

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14 pages, 1466 KiB  
Case Report
Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency
by Brianna L. Kline, Sylvie Jaillard, Katrina M. Bell, Shabnam Bakhshalizadeh, Gorjana Robevska, Jocelyn van den Bergen, Jérôme Dulon, Katie L. Ayers, John Christodoulou, Michel C. Tchan, Philippe Touraine, Andrew H. Sinclair and Elena J. Tucker
Genes 2022, 13(11), 2113; https://doi.org/10.3390/genes13112113 - 14 Nov 2022
Cited by 6 | Viewed by 1609
Abstract
The mitochondrial ribosome is critical to mitochondrial protein synthesis. Defects in both the large and small subunits of the mitochondrial ribosome can cause human disease, including, but not limited to, cardiomyopathy, hypoglycaemia, neurological dysfunction, sensorineural hearing loss and premature ovarian insufficiency (POI). POI [...] Read more.
The mitochondrial ribosome is critical to mitochondrial protein synthesis. Defects in both the large and small subunits of the mitochondrial ribosome can cause human disease, including, but not limited to, cardiomyopathy, hypoglycaemia, neurological dysfunction, sensorineural hearing loss and premature ovarian insufficiency (POI). POI is a common cause of infertility, characterised by elevated follicle-stimulating hormone and amenorrhea in women under the age of 40. Here we describe a patient with POI, sensorineural hearing loss and Hashimoto’s disease. The co-occurrence of POI with sensorineural hearing loss indicates Perrault syndrome. Whole exome sequencing identified two compound heterozygous variants in mitochondrial ribosomal protein 7 (MRPS7), c.373A>T/p.(Lys125*) and c.536G>A/p.(Arg179His). Both novel variants are predicted to be pathogenic via in-silico algorithms. Variants in MRPS7 have been described only once in the literature and were identified in sisters, one of whom presented with congenital sensorineural hearing loss and POI, consistent with our patient phenotype. The other affected sister had a more severe disease course and died in early adolescence due to liver and renal failure before the reproductive phenotype was known. This second independent report validates that variants in MRPS7 are a cause of syndromic POI/Perrault syndrome. We present this case and review the current evidence supporting the integral role of the mitochondrial ribosome in supporting ovarian function. Full article
(This article belongs to the Special Issue Molecular Genetics of Infertility)
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